They've been playing each other since 1960. And the Bills and Chargers have played some momentous games, including playoff games and AFL Championship match-ups.
The stakes are not quite as high this week, but it's an important game for the 2017 Buffalo Bills. Here are the top seven storylines for this week's Bills match-up with the Chargers:
1. MID-NOVEMBER MUST WIN?
It's all AFC games the rest of the way for the Bills so they hold their playoff destiny in their hands. And it's tough to envision a playoff push for Buffalo that doesn't include a win against the Chargers this week.
Of the Bills final seven games, four of them are against opponents with a losing record, and L.A. is one of them. After the Chargers, the Bills get the Chiefs and the Patriots back-to-back – two of the AFC'S bright lights.
The Bills will be looking to snap their first two-game losing streak this year and the Chargers know a lot about streaking. They started their season with four straight losses, then won three in a row. Now they're mired in a two-game losing streak of their own.
2. WILL PHILIP RIVERS KEEP ROLLING?
Quarterback Philip Rivers has been the face of the Chargers franchise for almost a decade and a half. But there's a chance the Bills might see his face on the sidelines instead of on the field Sunday.
Rivers came to the Chargers complex Monday and self-reported some concussion symptoms, and L.A. immediately put him in the concussion protocol. As of Monday night, Coach Anthony Lynn wasn't sure if Rivers will play Sunday, saying he hopes he's got a chance to play.
"Some players go through it in a week and they come out OK," Lynn said. "They practice Wednesday. We'll see where he's at."
If Rivers can't play, 12-year veteran Kellen Clemens is ready to step in.
"I feel fine about Kellen," Coach Lynn said this week. "He's well prepared, he's a veteran."
Rivers has not missed a start since he took over as the Chargers starter in 2006, a stretch of 185 games. It's the second-longest active streak behind Giants QB Eli Manning (208 games).
3. CAN THE BILLS BRING THE HEAT?
Whether it's Rivers or Clemens, the Bills would help themselves immensely by being able to pressure the passer. Buffalo is 30th in the NFL in sack percentage. In the last three games, they've managed a total of just one sack. The Chargers edge rushers, Joey Bosa and Melvin Ingram, have combined for 18 sacks already this year, more than the entire Bills team has recorded (14).
4. TRAMPLED BY THE RUN IN TWO STRAIGHT – BILLS HAVE TO FIX IT**
In the big picture, it's not sacks or pass defense, but run defense that's been the glaring problem in Buffalo's two-game slide. The Jets ran up big totals and the Saints surpassed them last week, going for 298 yards on the ground. It's the recipe for defensive disaster and the Bills are likely to make it their top priority to fix it this week.
Two weeks ago, the Bills were third in the NFL in run defense. They've dropped to 22nd now.
"Being in and out of our gaps was a big problem," according to defensive coordinator Leslie Frazier. "Why is it happening? We have to go back to the fundamentals of what we do and teach it as if we're at the beginning of training camp. We have to get back to the basics of run defense."
5. FAMILIAR FACES
There are a lot of Bills connections with the Chargers these days, and it starts with the coach and general manager. L.A. head coach Anthony Lynn spent the last two years with the Bills, as running backs coach, then offensive coordinator, before winding up as the interim head coach in last year's season finale.
Chargers general manager Tom Telesco is a Buffalo native who played at St. Francis High School in Athol Springs, a stone's throw away from New Era Field. He's a disciple of former Bills general manager and Hall of Famer Bill Polian.
There's also Chargers wide receiver coach Nick Sirianni, a native of Jamestown. Running back Branden "Bo" Oliver won many friends and admirers during his standout college career at the University at Buffalo.
6. UNFAMILIAR PLACES
The Bills head back to Los Angeles this week, the second year in a row they've played in La-La Land. But this is the first time they've played the Chargers in L.A. since November 20, 1960, when they beat Los Angeles 32-3 at the Coliseum.
This week, they're across town at the 27,000 seat Stub Hub Center in Carson, California. And a good portion of this Sunday's crowd may be cheering for the visitors.
Longtime Los Angeles Times Sportswriter Sam Farmer says some of the Chargers "home" games have been anything but this year, with fans of their opponents buying up unsold tickets.
"There just isn't a fan base for the Chargers in Los Angeles," Farmer said this week, in an appearance on The John Murphy Show.
"That sort of played itself out for the home games they had against Miami, Kansas City and Philadelphia," Farmer said. "The team (the Chargers) got booed when they came out on the field. It's like the Chargers are playing 16 road games."
Right now, the Bills will take any edge they can get.